HIV-1 infects target cells via a receptor complex formed by CD4 and a chemokine receptor, primarily CCR5 or CXCR4 (Berger, E. et al., Ann. Rev. Immunol. 17:657-700 (1999)). Commonly, HIV-1 transmission is mediated by CCR5-tropic variants, also designated slow/low, non-syncytia-inducer, or macrophage-tropic, which dominate the early stages of HIV-1 infection and frequently persist during the entire course of the disease (Fenyo, E. M. et al. J. Virol. 62:4414-9 (1988); Tersmette, M. et al. Lancet 1:983-5 (1989); Schuitemaker, H. et al. J. Virol. 66:1354-60 (1992); Fenyo, E. M. AIDS 7:1673-4 (1993); Koot, M. et al. Ann. Intern. Med. 118:681-688 (1993); Bjorndal, A. et al. J. Virol. 71:7478-87 (1997); Scarlatti, G. et al. Nature Med. 3:1259-65 (1997); Connor, R. I. et al., J. Exp. Med. 185:621-8 (1997)). In contrast, HIV-1 variants that use CXCR4 are typically detected at the later stages, and are associated with a rapid decline in CD4 T cells and progression to AIDS (Fenyo, E. M. et al., 1988, supra; Bjorndal, A. et al. J. Virol. 71:7478-87 (1997); Scarlatti, G. et al., 1997, supra; Connor, R. I. et al., 1997, supra; Fouchier, R. A. et al., Virology 219:87-95 (1996); Koot, M. et al. J. Infect. Dis. 179:254-8 (1999)). Disease progression is also associated with the emergence of concurrent infections that may affect the course of HIV disease by mechanisms that remain unknown.
Human herpesvirus 6 (HHV-6) is a double-stranded DNA virus originally isolated from immunocompromised patients with different lymphoproliferative disorders and described as a B-lymphotropic virus (Salahuddin, S. Z. et al., Science 234:596-601 (1986)). Shortly thereafter, however, a primary tropism for CD4+ T lymphocytes was documented both in vitro (Lusso, P. et al., J. Exp. Med. 167:1659-1670 (1988)) and in vivo (Takahashi, K. et al., J. Virol. 63:3161-3163 (1989)). Two major viral subgroups, designated A and B, have been defined, which form two segregated clusters with unique genetic, biologic and immunologic characteristics (Lusso, P. Antiviral Research, 31:1-21 (1996)). While HHV-6 B is highly prevalent in the human population in all geographic areas (Lusso, P. Antiviral Research, 31:1-21 (1996)), the epidemiology of HHV-6 A is still largely undefined. Primary infection with HHV-6 B, which occurs almost universally during early childhood, has been linked to the etiology of exanthema subitum, a usually benign febrile disease (Yamanishi, K. et al., Lancet i, 1065 (1988)). Conversely, little is known about the time and pathologic consequences of primary HHV-6 A infection.
In the adult, HHV-6 infection and/or reactivation have been associated with a wide variety of diseases, although most of these associations have not been substantiated by rigorous epidemiological and virological studies. Considerable interest was raised by recent data on a possible link between HHV-6 and multiple sclerosis (Challoner, P. B. et al., Proc. Natl. Acad. Sci. USA 92:7440-4 (1995)), but the evidence hitherto accumulated is controversial (Soldan, S. S. et al., Nat. Med. 3:1394-7 (1997); Martin C et al. Acta Neurol Scand; 95:280-283 (1997)). In immunocompromised people, HHV-6 acts as an opportunistic agent that may cause life-threatening infections of the respiratory tract and the central nervous system, as well as bone marrow and organ graft failure (Lusso, P. Antiviral Research, supra).
Several lines of evidence have led to speculation that HHV-6 may act as an immunosuppressive agent in vivo. Both HHV-6 subgroups induce severe thymocyte depletion in heterochimeric SCID hu thy/liv mice, showing a predominant tropism and cytopathicity for immature thymic precursor cells (Gobbi, A. et al., Journal of Experimental Medicine, 189:1953-1960 (1999)). Disseminated HHV-6 A and B coinfection has been linked with a progressive and ultimately fatal immunodeficiency syndrome in an HIV-negative child (Knox, K. K. et al., Clin. Infect. Dis. 20:406-13 (1995)). Moreover, active HHV-6 infection, as revealed by the detection of plasma viremia, was associated with lymphocytopenia and with defective lymphocyte proliferation to recall antigens in patients who received allogeneic stem cell transplantation. Consistent with these observations, it has been suggested that HHV-6, particularly subgroup A, may act as a cofactor in the progression of human immunodeficiency virus (HIV) disease, which might contribute, either directly or indirectly, to the depletion of CD4+ T cells and the other dysfunctions of the immune system associated with full-blown AIDS (Lusso, P. et al., Immunology Today 16:67-71 (1995)). It has also been suggested that HHV-6 down-regulates the CXCR4 receptor, making CD4+ lymphocytes resistant to T lymphocyte-tropic HIV-1 strains. (Yasukawa et al., J. Immunol. 162:5417-5422 (1999). Progress in this area of investigation has been hampered by the lack of reliable and easily accessible study models.